The long term objective of this proposal is to understand the potential of Neuropilin-2 (NRP-2) inhibitors as novel therapies against metastatic prostate cancer (PCa). We will specifically investigate how NRP-2 axis promotes PCa bone metastasis and confers therapy resistance to cancer cells. Metastatic PCa is lethal and is resistant to currently available therapies. Effective treatment against the metastatic disease can be achieved through a comprehensive understanding of the molecular players involved in this process. NRP-2 is a receptor for growth factors such as VEGF-C, VEGF-A, and semaphorin 3F. We have observed a high expression of NRP-2 in human PCa bone metastases suggesting it has a metastasis-specific role. Our preliminary results suggested a novel function of NRP-2 in maintaining endocytosis in PCa cells. We are particularly interested in exploring the potential link between the regulation of endocytosis by the NRP-2 axis and its role in inducing autophagy to facilitate therapy resistance in metastatic prostate cancer. Moreover, we observed an active NRP-2 axis in bone cells (osteoblasts and osteoclasts) following its stimulation of PCa. Our preliminary results indicated that the NRP-2 axis in bone can promote osteoblastic lesions, a characteristic of PCa bone metastasis. We therefore hypothesize that the activation of NRP-2 axis in both the cancer cells and the bone cells in stroma enhances not only the metastatic potential of PCa but also promotes osteoblastic lesions. Targeting the NRP-2 axis will be important to treat prostate cancer patients with bone metastasis. In Aim 1 of this proposed study, we will determine how NRP-2 and its downstream target, WDFY-1, regulates the process of endosome maturation in metastatic PCa. In Aim 2, we will delineate the molecular mechanisms of NRP-2-mediated autophagy and its implications for docetaxel resistance in metastatic prostate cancer. In aim 3, the involvement of NRP-2 axis in promoting differentiation of osteoblastic cells will be tested following stimulation by PCa cells. We will also determine whether NRP-2 axis in osteoclasts is activated by PCa. These experiments will therefore reveal the role of NRP-2 axis in PCa-induced osteoblastic activity and its involvement in inhibiting osteoclast function. We speculate that PCa induced NRP-2 axis in osteoblast and osteoclast cumulatively promotes osteoblastic metastasis. This proposal will elucidate the function of the NRP-2 axis in prostate cancer bone metastases and will evaluate the therapeutic potential of this axis. The inhibition of this target in combination with established treatment options such as docetaxel should offer a survival benefit for prostate cancer patients with bone metastasis.